1. Field of Invention
This invention relates to monoamine oxidase-B (MAO-B) inhibitory 5-substituted 2,4-thiazolidinediones, pharmaceutical compositions thereof, process of preparation, and methods of use in mammals to treat cognitive disorders, neurological dysfunction, and/or mood disturbances such as, but not limited to degenerative nervous system diseases.
2. Background
Increasingly there is a need for effective treatments for nervous system disorders and neurological deficiencies. Many of these diseases correlate with increasing age due mainly to degenerative changes in the nervous systems. Although in early stages of some diseases, certain systems are rather specifically affected (e.g., cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.), multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's Disease, mental retardation, etc. This explains the generally observed multiple symptomatology that includes cognitive, neurological, and effective/psychotic components (see Gottfries, Psychopharmacol., 86:245 (1985)).
Monoamine oxidase (MAO, EC 1.4.3.4) is an enzyme responsible for the oxidative deamination of a variety of exogenous and endogenous amines such as phenylethylamine, dopamine, serotonin, adrenaline, noradrenaline. Johnson, Biochem. Pharmacol., 17, 1285-1297 (1968) disclosed that the enzyme exist in two forms, MAO-A and MAO-B, differing in tissue distribution, structure, and substrate specificity. Some of the natural substrates for MAO-A are serotonin, octopamine, adrenaline, and noradrenaline; and some of the substrates for MAO-B are dopamine, phenylethylamine, and tyramine. MAO-B is found primarily in the platelets and the brain, and appears to increase with age. Additionally, MAO-B is significantly higher in the brains of patients with Alzheimer's Disease associated dementia (Dostert, et al., Biochem. Pharmacol., 38:555-561 (1989)). Because MAO-B is primarily responsible for the degradation of the needed neurotransmitter, dopamine, Dostert suggests that there is a rationale for the use of selective MAO-B inhibitors for the treatment of dementia and Parkinson's disease (see Strolin and Dostert in "New Directions in Effective Disorders", Eds B. Lerer and S. Gershon, Springer, New York, 262-267; and GOttfries, CG, Psychopharacol., 86:245-252 (1985)).
The most pertinent literature citations and patent references related to this invention can be found in:
Gates, KS and Silverman, RB, "5-(Aminomethyl)-3-aryl-2-oxazolidione. A Novel Class of Mechanism-Based Inactivators of Monoamine Odidase", J. Am Chem Soc., 112:9364-9372 (1990); ##STR2##
Tipton, KF, et al., "The Enzyme-Activated Irreversible Inhibition of Type-B Monoamine Oxidase by 3-{4-[(3-Chlorophenyl)methoxy]phenyl}-5-[(methylamino)methyl]-2-Oxazolidin one Methanesulphonate (Compound MD 780236) and the Enzyme-Catalysed Oxidation of this Compound as Competing Reactions", Biochem J., 209:235-242 (1983);
Dostert, et al., "Different Stereoselective Inhibition of Monoamine Oxidase-B by the R- and S-Enantiomers of MD 780236", J. Pharm. Pharmacol., 35:161-165 (1983); Drugs of the Future, 9(8):585-586 (1984); ##STR3##
"New benzyl-thiazolidine-dione derivatives for prevention and treatment of hyperglycemia, diabetes II, hyperlipidemia, hypertension, cardiovascular disease, and eating disorders", Beecham Group PLC, EP 419-035-A, (Aug. 25, 1989). ##STR4## where A.sub.1 =optionally substituted aromatic heterocyclic group;
A.sub.2 =benzene ring with up to 5 substitutions; PA1 X=O, S, or NR.sub.1 ; PA1 R.sub.1 =H, alkyl, acyl optionally substituted, aryl or optionally substituted aryl and aralkyl; PA1 Y=0 or S; PA1 R.sub.2 =alkyl, aralkyl, or aryl; PA1 n=2 to 6 PA1 R.sup.3 =H, alkyl; PA1 R.sup.4, R.sup.5 =H; PA1 R.sup.4 R.sup.5 =bond; PA1 R.sup.5, R.sup.6 =H, or one of R.sup.6,R.sup.7 =H, the other=OH, SMe; PA1 R.sup.5 R.sup.6 =S, O; PA1 X=SO.sub.n ; PA1 n=0-2. PA1 Y=O or if X=O; may be S; PA1 R.sub.1 =H, Cl, Br, CF.sub.3, CN, or NMe.sub.2 ; and PA1 R.sub.2 =H or Cl. PA1 R.sup.2 =H, or 1-4C alkyl; PA1 R.sup.3 =H or 1-2C alkyl; and PA1 n=0-3. PA1 R.sup.1 is H, halo, C.sub.1 to C.sub.10 alkyl, alkenyl, alkynyl, bicycloalkyl, aryl optionally substituted with 1-2 substituents independently selected from the group within the definition for R.sup.2, --C(.dbd.O)NR.sup.2, --C(.dbd.O)OR.sup.2, --CHO, --CN, --NO.sub.2, --N(R.sup.2).sub.2, NR.sup.2 C(.dbd.O)R.sup.2, --NR.sup.2 C(.dbd.O)OR.sup.2, --NR.sup.2 C(.dbd.O)N(R.sup.2).sub.2, --NR.sup.2 SO.sub.2 R.sup.2, --OR.sup.2, --OC(.dbd.O)OR.sup.2, --OC(.dbd.O)N(R.sup.2).sub.2, --SO.sub.2 N(R.sup.2).sub.2 ; PA1 n is 1 to 6; PA1 X is --CHR.sup.2, --NR.sup.2, O, or --S(O)p; PA1 p is 0, 1, or 2; PA1 a is a double bond; PA1 m is 1 to 6; PA1 Y is --OR.sup.2, --NHR.sup.2, --NR.sup.2 R.sup.3, --CN, --COR.sup.2, --C0.sub.2 R.sup.2, --S(O)pR.sup.2, or --SCN; PA1 R.sup.2 and R.sup.3 are independently H, alkyl of 1 to 6 carbon atoms, aryl, acyl or alkaryl of 1 to 10 carbon atoms; with the proviso that when m is 1, then Y is not OH, and when m is 2, and Y is NR.sup.2 R.sup.3, then R.sup.2 and R.sup.3 cannot simultaneously be alkyl. PA1 A is a straight or branched alkyl chain of 1 to 10 carbon atoms, phenyl optionally substituted with 1-3 substituents independently selected from the group within the definition for R.sup.1, pyridyl, or naphthyl; PA1 X is O; and PA1 Y is --CN, --COR.sup.2, --CO.sub.2 R.sup.2, --S(O)pR.sup.2, or --SCN. PA1 A is phenyl or 2-, 3-, or 4-chlorophenyl; 2-, 3-, or 4-pyridyl; PA1 X is O; PA1 Y is CN, SCN, or C0.sub.2 R.sup.2 where R.sup.2 is alkyl of 1 to 4 carbon atoms. PA1 a. 2,4-Dioxo-5-[3-(phenylmethoxy)-phenylmethylene]-4- thiazolidinebutanenitrile b. 2,4-Dioxo-5-[3-(phenylmethoxy)-phenylmethylene]-4-thiazolidinepentanenitri le PA1 R.sup.1 is halo, C.sub.1 to C.sub.10 alkyl, alkenyl, alkynyl, bicycloalkyl, aryl optionally substituted with 1-2 substituents independently selected from the group within the definition for R.sup.2, --C(.dbd.O)NR.sup.2, --C(.dbd.O)OR.sup.2, --CHO, --CN, --NO.sub.2, --N(R.sup.2).sub.2, --NR.sup.2 C(.dbd.O)R.sup.2, --NR.sup.2 C(.dbd.O)OR.sup.2, --NR.sup.2 C(.dbd.O)N(R.sup.2).sub.2, --NR.sup.2 SO.sub.2 R.sup.2, --OR.sup.2, --OC(.dbd.O)OR.sup.2, --OC(.dbd.O)N(R.sup.2).sub.2, --SO.sub.2 N(R.sup.2).sub.2, --S(O)R.sup.2, and --SO.sub.2 R.sup.2 ; PA1 X is --CHR.sup.2, --NR.sup.2, O, or --S(O)p; PA1 p is 0, 1, or 2; PA1 a is a single or double bond; PA1 m is 0 to 6; PA1 Y is H, --OR.sup.2, --NHR.sup.2, --NR.sup.2 R.sup.3, --CN, --COR.sup.2, --CO.sub.2 R.sup.2, --S(O)pR.sup.2, or --SCN; and PA1 R.sup.2 and R.sup.3 are independently H, alkyl of 1 to 6 carbons, aryl, acyl or alkaryl of 1 to 10 carbon atoms; Preferred methods utilize those compounds of Formula I wherein: PA1 A is a straight or branched alkyl chain of 1 to 10 carbons, phenyl optionally substituted with 1-3 substituents independently selected from the group within the definition for R.sup.1, pyridyl, or naphthyl; PA1 X is O; and PA1 Y is H, --CN, --COR.sup.2 --CO.sub.2 R.sup.2, --S(O)pR.sup.2, or --SCN, with the proviso that PA1 A is phenyl or 2-, 3-, or 4-chlorophenyl; 2-, 3-, or 4-pyridyl; PA1 X is O; PA1 Y is H, --CN, --SCN, or --CO.sub.2 R.sup.2 where R.sup.2 is alkyl of 1 to 4 carbons; with the proviso that
Sohda, T., et al., "Studies on Antidiabetic Agents. Synthesis and Biological Activities of Pioglitazone and Related Compounds", Chem. Pharm. Bull., 39(6):1440-1445 (1991). ##STR5##
Sohda, T., et al., Chem Pharm. Bull., 30:3580 (1982). ##STR6##
Panetta in EP 391644 disclosed 5-(4-hydroxyphenyl)-2-thioxo-4-thiazolidinones as antiinflammatories. ##STR7## where R.sup.1, R.sup.2 =H, alkyl, alkoxy, alkylcarbonyloxyalkyl;
Patent NL-7300982-Q teaches that 3-hydroxymethyl-5-benzylidene-azolidinones are anti-arthritics, anti-rheumatics, and immunosuppressants, and can be represented by the following formula: ##STR8## where X=O or S;
Patent JA 3077-875-A described a series of 3-carboxalkyl-thiazolidine-2,4-dione derivatives as aldose reductase inhibitors for treating diabetic complications, that can be represented by the formula: ##STR9## where R.sup.1 =1-8C alkyl or 3-6C cycloalkyl;
None of these references teach or suggest the compounds act as MAO-B inhibitors or that they are useful for treating memory disorders.